G-quadruplex stabilization provokes DNA breaks in human PKD1, revealing a second hit mechanism for ADPKD.

The "secondhit" pathway is responsible for biallelic inactivation of many tumor suppressors, where a pathogenic germline allele is joined by somatic mutation of the remaining functional allele. The mechanisms are unresolved, but the human PKD1 tumor suppressor is a good experimental model for identifying the molecular determinants. Inactivation of PKD1 results in autosomal dominant polycystic kidney disease, a very common disorder characterized by the accumulation of fluid-filled cysts and end-stage renal disease.

Turning green: the impact of changing to more eco-friendly respiratory healthcare - a carbon and cost analysis of Dutch prescription data.

Objectives: Dry powder inhalers (DPIs) and soft mist inhalers have a substantially lower global warming potential than pressurised metered-dose inhalers (pMDIs). To help mitigate climate change, we assessed the potential emission reduction in CO equivalents when replacing pMDIs by non-propellant inhalers (NPIs) in Dutch respiratory healthcare and estimated the associated cost.

Design: We performed a descriptive analysis of prescription data from two national databases of two independent governmental bodies.

Small-diameter artery decellularization: Effects of anionic detergent concentration and treatment duration on porcine internal thoracic arteries.

Engineered replacement materials have tremendous potential for vascular applications where over 400,000 damaged and diseased blood vessels are replaced annually in the United States alone. Unlike large diameter blood vessels, which are effectively replaced by synthetic materials, prosthetic small-diameter vessels are prone to early failure, restenosis, and reintervention surgery. We investigated the differential response of varying 0%-6% sodium dodecyl sulfate and sodium deoxycholate anionic detergent concentrations after 24 and 72 h in the presence of DNase using biochemical, histological, and biaxial mechanical analyses to optimize the decellularization process for xenogeneic vascular tissue sources, specifically the porcine internal thoracic artery (ITA).

Rational selection of inhalation devices in the treatment of chronic obstructive pulmonary disease by means of the System of Objectified Judgement Analysis (SOJA).

Objectives: The large number of available medicines and devices makes it almost impossible to have sufficient knowledge of each individual medicine and device, especially for general practitioners. This may lead to suboptimal treatment, more exacerbations, hospitalisations and higher treatment costs. Reducing the number of medicines and devices, based on rational criteria, allows physicians and pharmacists to build experience with a more limited set of medicines and to standardise the inhalation instructions.

Healthcare and disease burden among refugees in long-stay refugee camps at Lesbos, Greece.

Objectives: To assess current medical problems at two Greek refugee sites at Lesbos island (Camp Moria and Caritas hotel), to explore which care is needed and to assess how the provided healthcare can be improved.

Design: In this dynamic cohort study all consecutive patients who visited doctors from the Boat Refugee Foundation were included.

Outcome: Treatment Rates (TR) with 95% Confidence Intervals (95% CI) were calculated for all major health issues.

Management of children with solid organ injuries after blunt torso trauma.

Background: Management of children with intra-abdominal solid organ injuries has evolved markedly. We describe the current management of children with intra-abdominal solid organ injuries after blunt trauma in a large multicenter network.

Methods: We performed a planned secondary analysis of a prospective, multicenter observational study of children (<18 years) with blunt torso trauma.

Accuracy of the abdominal examination for identifying children with blunt intra-abdominal injuries.

Objective: To determine the accuracy of complaints of abdominal pain and findings of abdominal tenderness for identifying children with intra-abdominal injury (IAI) stratified by Glasgow Coma Scale (GCS) score.

Study Design: This was a prospective, multicenter observational study of children with blunt torso trauma and a GCS score ≥13. We calculated the sensitivity of abdominal findings for IAI with 95% CI stratified by GCS score.

Sensitivity of plain pelvis radiography in children with blunt torso trauma.

Study Objective: Plain anteroposterior pelvic radiographs are commonly used to screen children for pelvic fractures or dislocations after blunt torso trauma. The test sensitivity and utility, however, are unclear. We assessed the sensitivity of anteroposterior pelvic radiographs for identifying children with pelvic fractures or dislocations after blunt torso trauma.

Occult pneumothoraces in children with blunt torso trauma.

Objectives: Plain chest x-ray (CXR) is often the initial screening test to identify pneumothoraces in trauma patients. Computed tomography (CT) scans can identify pneumothoraces not seen on CXR ("occult pneumothoraces"), but the clinical importance of these radiographically occult pneumothoraces in children is not well understood. The objectives of this study were to determine the proportion of occult pneumothoraces in injured children and the rate of treatment with tube thoracostomy among these children.

Identifying children at very low risk of clinically important blunt abdominal injuries.

Study Objective: We derive a prediction rule to identify children at very low risk for intra-abdominal injuries undergoing acute intervention and for whom computed tomography (CT) could be obviated.

Methods: We prospectively enrolled children with blunt torso trauma in 20 emergency departments. We used binary recursive partitioning to create a prediction rule to identify children at very low risk of intra-abdominal injuries undergoing acute intervention (therapeutic laparotomy, angiographic embolization, blood transfusion for abdominal hemorrhage, or intravenous fluid for ≥2 nights for pancreatic/gastrointestinal injuries).

[Metal fume fever, often unrecognized].

Background: Metal fume fever is an occupational disease caused by inhalation of volatile metal oxides. Clinically there is a strong resemblance to influenza. It is thought that metal fume fever occurs much more frequently than it is reported.

An asymmetric synthesis of (2S,5S)-5-substituted azepane-2-carboxylate derivatives.

To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large scale preparation. To this end we have successfully developed a scalable asymmetric synthesis of these derivatives that starts with known hydroxy-ketone 8.

HbA1c measurements from dried blood spots: validation and patient satisfaction.

Background: This study evaluates HbA1c measurements from dried blood spots collected on filter paper and compares HbA1c from filter paper (capillary blood) with HbA1c measured in venous blood.

Methods: Patient satisfaction was evaluated using a questionnaire. The performance with the filter paper method was assessed by comparing HbA1c results from EDTA-blood samples obtained via dried blood spots with HbA1c results obtained with freshly hemolyzed blood (routine HbA1c).

A new function of human HtrA2 as an amyloid-beta oligomerization inhibitor.

Human HtrA2 is part of the HtrA family of ATP-independent serine proteases that are conserved in both prokaryotes and eukaryotes and localizes to the intermembrane space of the mitochondria. Several recent reports have suggested that HtrA2 is important for maintaining proper mitochondrial homeostasis and may play a role in Alzheimer's disease (AD), which is characterized by the presence of aggregates of the amyloid-beta peptide 1-42 (Abeta1-42). In this study, we analyzed the ability of HtrA2 to delay the aggregation of the model substrate citrate synthase (CS) and of the toxic Abeta1-42 peptide.

Role of the PDZ domains in Escherichia coli DegP protein.

PDZ domains are modular protein interaction domains that are present in metazoans and bacteria. These domains possess unique structural features that allow them to interact with the C-terminal residues of their ligands. The Escherichia coli essential periplasmic protein DegP contains two PDZ domains attached to the C-terminal end of the protease domain.

The economic burden associated with prior authorizations in an allergist office.

Costs for managed care organizations to process prior authorizations (PAs) for nonformulary medications have been estimated to be dollars 20-25 per request. Costs for physicians to process these requests have not been studied extensively. A data collection tool was developed and used by physicians and nurses to document time spent on processing PAs.

Stereoselective and efficient synthesis of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol.

[reaction: see text] Two short and efficient synthesis routes have been developed for bis-THF-alcohol 2, a key building block of the investigational HIV protease inhibitor TMC114 (1). Using S-2,3-O-isopropylideneglyceraldehyde (4) as the source of chirality, both routes are based on a diastereoselective Michael addition of nitromethane to give predominantly the syn congeners 6 followed by a Nef oxidation and cyclization to afford lactone acetals 8, which are reduced and cyclized to give 2.

Effects of fenoterol on beta-adrenoceptor and muscarinic M2 receptor function in bovine tracheal smooth muscle.

Prolonged (18 h) incubation of isolated bovine tracheal smooth muscle with the beta2-adrenoceptor agonist fenoterol (10 microM) induced desensitization of isoprenaline-induced adenylyl cyclase activity in bovine tracheal smooth muscle membranes, characterized by a 25% decrease in maximal effect (Emax) (P < 0.05), while the sensitivity to the agonist (pEC50) was unchanged. The Emax value of isoprenaline-induced smooth muscle relaxation of submaximal methacholine-induced contractile tones was similarly reduced by about 25% (P < 0.

Enabling children: participation as a new perspective on child-health promotion.

As fellow citizens, all children need a stimulating social environment that helps them develop self-respect and social competence. Developmental research, however, shows, that many children do not or cannot fulfil the social, moral or cognitive developmental tasks which are necessary for healthy development. A lack of opportunities for gaining meaningful social experiences can be seen as a major source of psychosocial and behavioural problems in children.

The Family Approach to the Resolution of Racemates .

The resolution of racemates is revolutionized with the method presented here, in which mixtures ("families") of structurally and stereochemically related resolving agents are used to precipitate salts of acidic or basic racemates rapidly and dependably. The racemate is usually separated in a single operation into enantiomers-the enantiomeric excesses and yields are good to excellent. Reagent mixtures with racemic or achiral components have also been developed.

A conserved helicase motif of the AddA subunit of the Bacillus subtilis ATP-dependent nuclease (AddAB) is essential for DNA repair and recombination.

Various mutations were introduced in a conserved helicase domain (motif VI) of the AddA subunit of the Bacillus subtilis ATP-dependent nuclease (AddAB) by site-directed mutagenesis. These mutations affected the helicase activity and the ATP-dependent exonuclease activity on double-stranded DNA (dsDNA) as the substrate to various degrees, but had hardly any effect on the exonuclease activity on single-stranded DNA (ssDNA), suggesting that exonuclease activity on dsDNA of the enzyme requires unwinding of the DNA. This idea was supported by the finding that, initially, the rate and extent of unwinding of the DNA were higher than those of its degradation to acid-soluble products by the exonucleolytic activity.

Regulated expression of the dinR and recA genes during competence development and SOS induction in Bacillus subtilis.

It has been hypothesized that the dinR gene product of Bacillus subtilis acts as a repressor of the SOS regulon by binding to DNA sequences located upstream of SOS genes, including dinR and recA. Following activation as a result of DNA damage, RecA is believed to catalyse DinR-autocleavage, thus derepressing the SOS regulon. The present results support this hypothesis: a dinR insertion mutation caused a high, constitutive expression of both dinR and recA, which could not be further elevated by SOS-induction.

Replacement of the lysine residue in the consensus ATP-binding sequence of the AddA subunit of AddAB drastically affects chromosomal recombination in transformation and transduction of Bacillus subtilis.

The ATP-dependent deoxyribonuclease enzyme complex (AddAB) of Bacillus subtilis possesses two consensus ATP-binding sequences, located in the N-terminal region of both subunits. The highly conserved lysine residues in both consensus ATP-binding sequences were replaced by glycine, resulting in the mutant enzyme complexes AddAB-A-K36G (AddA*B) and AddAB-B-K14G (AddAB*). The mutation in subunit AddA reduced DNA repair and chromosomal transformation, and abolished bacteriophage PBS1-mediated transduction.

Effects of lysine-to-glycine mutations in the ATP-binding consensus sequences in the AddA and AddB subunits on the Bacillus subtilis AddAB enzyme activities.

The N-terminal regions of both subunits AddA and AddB of the Bacillus subtilis AddAB enzyme contain amino acid sequences, designated motif I, which are commonly found in ATP-binding enzymes. The functional significance of the motif I regions was studied by replacing the highly conserved lysine residues of the regions in both subunits by glycines and by examination of the resulting mutant enzymes with respect to their enzymatic properties. This study shows that the mutation in subunit AddB hardly affected the ATPase, helicase, and exonuclease activities of the AddAB enzyme.